Patient perceptions of symptoms and concerns during cancer chemotherapy: 'affects my family' is the most important.

BACKGROUND: Cancer chemotherapy is associated with a variety of side effects/adverse events. It is very important that patients adhere to the planned chemotherapy regimen, which necessitates a minimum of side effects and that these side effects be kept under control. We have investigated patients' concerns and symptoms during chemotherapy with the aim to seek solutions that will improve patients' quality of life during chemotherapy. METHODS: Forty-nine patients with malignant diseases on parenteral antineoplastic agents were sequentially enrolled in this study. These patients completed a questionnaire consisting of 42 items related to non-physical concerns and 52 items of physical symptoms related to chemotherapy. Each patient was also asked to select the three items among these 94 items which affected him/her the most. RESULTS: The median age of the cancer patients was 62 years and the male-to-female ratio was 18:31. Among the non-physical concerns, the most frequently chosen concern was 'affects my family or partner,' followed by anxiety related to treatment. Regarding the physical symptoms, the most frequent complaints were fatigue, alopecia and constipation, while the most troublesome symptoms were nausea, poor taste and paresthesia. Overall, the most frequently expressed concerns were 'affects my family or partner' and anxiety related to treatment. Male patients suffered most from fever, fatigue and nausea, and female patients complained more of poor taste and gastrointestinal problems. CONCLUSION: Patient perceptions of adverse events associated with cancer chemotherapy apparently have changed from physical symptoms to non-physical concerns. In our patient cohort 'affects my family or partner' was the most important concern. One important point to note is that female patients often complained of poor taste because this meant they were unable to cook well.

Interleukin 4 suppresses the spontaneous growth of chronic myelomonocytic leukemia cells.

We studied the effects of IL-4 on the spontaneous proliferation of chronic myelomonocytic leukemia (CMMoL) cells in vitro. IL-4 (100 U/ml) suppressed the spontaneous DNA synthesis by approximately 50% in 5 of 8 cases examined. IL-4 (100 U/ml) also inhibited the spontaneous colony formation by CMMoL cells in a methylcellulose culture by 50-97% in all of the 10 cases in which spontaneous colonies were formed. This IL-4-mediated suppression of the growth of CMMoL cells was completely abolished by the addition of anti-IL-4 neutralizing antibodies. The spontaneous CMMoL colonies were substantially suppressed by the addition of either anti-IL-6 or anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) antibodies to the colony assay system: the addition of both anti-IL-6 and anti-GM-CSF antibodies resulted in greater than 80% inhibition of the colony formation by CMMoL cells. On the other hand, none of anti-IL-1-beta, anti-granulocyte-CSF, anti-macrophage-CSF, or anti-tumor necrosis factor-alpha antibodies affected the CMMoL colony formation. In the supernatants from 24-h cultures of CMMoL cells, high levels of IL-6 and GM-CSF were demonstrated in 9 of 9 and 2 of 9 cases examined, respectively. IL-4 (100 U/ml) almost completely inhibited the secretion of IL-6 and GM-CSF by CMMoL cells. These observations suggest that IL-4 suppresses the spontaneous proliferation of CMMoL cells by inhibiting their production of IL-6 and/or GM-CSF, both of which could act in vitro as an autocrine growth factor for CMMoL cells.

Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology.

Diagnosis and treatment of bone metastasis requires various types of measures, specialists and caregivers. To provide better diagnosis and treatment, a multidisciplinary team approach is required. The members of this multidisciplinary team include doctors of primary cancers, radiologists, pathologists, orthopaedists, radiotherapists, clinical oncologists, palliative caregivers, rehabilitation doctors, dentists, nurses, pharmacists, physical therapists, occupational therapists, medical social workers, etc. Medical evidence was extracted from published articles describing meta-analyses or randomised controlled trials concerning patients with bone metastases mainly from 2003 to 2013, and a guideline was developed according to the Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Multidisciplinary team meetings are helpful in diagnosis and treatment. Clinical benefits such as physical or psychological palliation obtained using the multidisciplinary team approaches are apparent. We established a guideline describing each specialty field, to improve understanding of the different fields among the specialists, who can further provide appropriate treatment, and to improve patients' outcomes.

Identification of an alternative form of the Drosophila Ca2+/calmodulin-dependent protein kinase II that is maternally derived.

Four forms of the Drosophila Ca2+/calmodulin-dependent protein kinase II are generated from a single gene by alternative splicing (Ohsako et al. (1993) J. Biol. Chem. 268, 2052-2062). We identified a fifth form of the cDNA encoding the enzyme expressed in the ovary, unfertilized egg and early embryos by reverse transcription-polymerase chain reaction, which suggests that it is maternally derived. The fifth form was also generated from the gene by alternative splicing and was identical to the cDNA encoding the 530-amino-acid polypeptide, the longest of the four forms previously identified, except that it lacked exon 11. Three splicing derivatives which lost one amino acid from the 509- and 530-amino-acid polypeptides were also found in 4 to 10 h embryos.

A pregnant woman with anti-Gregory antigen: case report.

Negative Gregory antigen (Gy(a-)) remains an extremely uncommon blood phenotype. We describe a 32-year-old pregnant woman with (Gy(a-)) and anti-Gregory antigen (anti-Gy(a)). There was no evidence of consanguineous mating in her family. Blood typing study revealed that only her father was Gy(a-) among the family. Anti-Gy(a) had a titer of 16 before pregnancy, but increased to 1024 at 33 weeks of gestation with a titer of 512 at 34 weeks. Her own blood stores were collected starting at 14 weeks, amounting to 1800 g totally. She underwent an emergency cesarean section at 35 weeks due to a non-reassuring fetal status. Blood loss was approximately 1090 g. Cord blood type was found to be Gy(a-). The indirect Coombs test of cord blood was positive, while the direct Coombs test was negative. No neonatal hemorrhagic disease developed. The storage of a sufficient amount of crossmatch-compatible Gy(a-) blood during pregnancy is important in case of possible need of blood transfusion at delivery for women with anti-Gy(a).

Relationship of infused CFU-GM and CFU-Mk mobilized by chemotherapy with or without G-CSF to platelet recovery after autologous blood stem cell transplantation.

Although hematologic reconstitution is usually rapid after autologous blood stem cell transplantation (ABSCT), there is an occasional delay in platelet recovery. We studied the hematologic recovery of 27 adult patients with hematologic malignancies who received marrow-ablative chemotherapy and ABSCT to determine whether or not the numbers of infused mononuclear cells (MNC), colony-forming units granulocyte/macrophage (CFU-GM), and colony-forming units megakaryocyte (CFU-Mk) were related to the speed of platelet recovery after ABSCT. Peripheral blood stem cells were collected using chemotherapy-induced mobilization with or without cytokine therapy. While the number of MNC infused did not show a significant correlation with time to platelet recovery as well as granulocyte and reticulocyte recovery, the logarithmic number of CFU-GM-infused did (p < 0.01). We also found a significant correlation between the logarithmic number of CFU-Mk-infused and the time to platelet recovery (p < 0.01). These findings suggest that the number of CFU-GM-infused is a reliable indicator of hematopoietic recovery and that the number of CFU-Mk-infused is no more reliable than CFU-GM for predicting platelet recovery after ABSCT.

Improvement of learning and increase in dopamine level in the frontal cortex by methylphenidate in mice lacking dopamine transporter.

The symptoms of attention-deficit/hyperactivity disorder (ADHD) are characterized by inattention and hyperactivity-impulsivity. It is a common childhood neurodevelopmental disorder that often persists into adulthood. Improvements in ADHD symptoms using psychostimulants have been recognized as a paradoxical calming effect. The psychostimulant methylphenidate (MPH) is currently used as the first-line medication for the management of ADHD. Recent studies have drawn attention to altered dopamine-mediated neurotransmission in ADHD, particularly reuptake by the dopamine transporter (DAT). This hypothesis is supported by the observation that DAT knockout mice exhibit marked hyperactivity that is responsive to acute MPH treatment. However, other behaviors relevant to ADHD have not been fully clarified. In the present study, we observed learning impairment in shuttle-box avoidance behavior together with hyperactivity in a novel environment in DAT knockout mice. Methylphenidate normalized these behaviors and enhanced escape activity in the tail suspension test. Interestingly, the effective dose of MPH increased extracellular dopamine in the prefrontal cortex but not striatum, suggesting an important role for changes in prefrontal dopamine in ADHD. Research that uses rodent models such as DAT knockout mice may be useful for elucidating the pathophysiology of ADHD.

Carbonyl (phenone) reductase in human liver: inter-individual variability.

The enzyme family carbonyl reductase, which catalyses the reduction of xenobiotic as well as endogenous ketones and aldehydes, has not been very well studied in terms of its biological functions and structural aspects. The aim of the present study was to check for the occurrence of inter-individual variability of carbonyl reductase activity in human liver. In vitro metabolism of p-nitroacetophenone (PNAP, a prototype substrate) indicated the presence of a high- and low-affinity enzyme site. The reductase activity of 17 kidney donor livers was screened at two concentrations (0.05 and 0.5 mM PNAP, below and above Km). The rates of reductase activity at 0.05 mM suggested a normal distribution. In contrast, at 0.5 mM the rates indicated a non-normal distribution, i.e. bi- or tri-modality. As an index of variability of enzyme affinity, ratios of velocities at 0.5 to 0.05 mM PNAP were calculated in order to check their frequency distributions. Three out of 17 kidney donor livers showed an atypical ratio. In these three cases, the high ratio was due to the low activity of the high affinity form of carbonyl reductase. Autopsy livers are a more readily available tissue source and about half the activity of the kidney donor livers was found in 43 autopsy livers indicating that they are a useful source of human tissue for studies of carbonyl reductase.

Successful second autologous blood stem cell transplantation after G-CSF-combined conditioning for the treatment of high-risk acute myelogenous leukemia.

We describe a patient with acute myelogenous leukemia (AML) who received his second autologous blood stem cell transplantation (ABSCT) following a G-CSF-combined pre-transplant conditioning regimen. The patient underwent ABSCT during first remission but suffered a relapse 8 months later. After achieving second remission, he was prepared for his second ABSCT; recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered in combination with Ara C, in addition to the same conditioning regimen as that used before the first ABSCT. There was no increase in regimen-related toxicity after this second G-CSF-combined conditioning regimen when compared with that observed after the first ABSCT. To date, the patient's second remission following the second ABSCT has lasted 26 months, which has exceeded that following the first ABSCT. The G-CSF-combined pretransplant conditioning regimen for ABSCT may be effective in the treatment of high-risk AML by increasing the chemosensitivity of the residual leukemic cells.

Intravenous cyclosporine and tacrolimus caused anaphylaxis but oral cyclosporine capsules were tolerated in an allogeneic bone marrow transplant recipient.

A Japanese female patient with angioimmunoblastic T cell lymphoma underwent allogeneic bone marrow transplantation (BMT) from her brother. Cyclosporine at a dose of 3 mg/kg was started by continuous infusion over 24 h on day -1 of BMT. Within a couple of minutes after the infusion was begun, she developed diffuse pruritic erythema on her whole body and tachycardia. The infusion was immediately stopped and corticosteroid was given, resulting in disappearance of the erythema gradually. She was then switched to intravenous tacrolimus. However, she suffered urticalial erythema again. Since polyoxyethylated castor oil, a solubilizer used in the injective formulation of both cyclosporine and tacrolimus, is considered to be responsible for the reaction, she was given oral capsules of cyclosporine (Sandimmun) in which polyoxyethylated castor oil was not contained. No further anaphylactic reaction was observed. The BM cells were successfully engrafted without causing severe GVHD. She was discharged on cyclosporine capsules without any further adverse effects. Anaphylaxis to intravenous cyclosporine and tacrolimus is a very rare but a serious complication. Our present case indicates that oral capsule of Sandimmun is a safe alternative to prevent GVHD in such a case of anaphylactic reaction against intravenous formulation.

Cyclosporine combined with methylprednisolone or methotrexate in prophylaxis of moderate to severe acute graft-versus-host disease.

To evaluate the efficacy of cyclosporine (CYA) regimens in preventing moderate to severe acute graft-versus-host disease (GVHD), 25 patients received immunosuppressive therapy consisting of either CYA and methylprednisolone or CYA and methotrexate (MTX) and the incidence and severity of acute GVHD was compared. These patients had leukemia or myelodysplastic syndrome (MDS) and received bone marrow transplants (BMT) from genotypically HLA-identical siblings. The incidence of grade I-IV acute GVHD in patients on the CYA/methylprednisolone regimen was 64% (7 of 11) compared with 50% (7 of 14) in those on the CYA/MTX regimen. Five of 11 patients with the CYA/methylprednisolone regimen developed moderate to severe acute GVHD (grade II-IV), fatal in 3 cases. No patient on the CYA/MTX regimen developed moderate to severe acute GVHD. Engraftment was faster in the CYA/methylprednisolone group than in the CYA/MTX group. The incidence of toxicity observed soon after BMT was comparable between groups. The CYA/MTX regimen may be superior to the CYA/methylprednisolone regimen for preventing moderate to severe acute GVHD.

Effects of macrophage colony-stimulating factor (M-CSF) on the mobilization of peripheral blood stem cells.

We studied the effects of human urinary macrophage colony-stimulating factor (huM-CSF) on the mobilization of peripheral blood stem cells (PBSC) following cytotoxic chemotherapy in 6 patients with acute leukemia. After complete remission (CR) was achieved, two courses of consolidation chemotherapy consisting of an intermediate dose of cytosine arabinoside were administered to the patients. During a recovery phase after each course of consolidation chemotherapy, two successive cycles of leukapheresis were performed every other day. M-CSF was administered intravenously at a dose of 8 x 10(6) U/day during a recovery phase after the second course of consolidation chemotherapy (cytotoxic plus M-CSF mobilization). There was no significant difference in white blood cell (WBC) or platelet recovery between the first and second cycles, regardless of the administration of M-CSF. Furthermore, between cytotoxic and cytotoxic/M-CSF mobilization, significant differences were not observed in the harvest of mononuclear cells (average 1.43 x 10(8)/kg vs 1.62 x 10(8)/kg), granulocyte/macrophage progenitor cells (CFU-GM) (1.82 x 10(4)/kg vs 3.07 x 10(4)/kg) or erythroid progenitor cells (BFU-E) (2.86 x 10(4)/kg vs 2.66 x 10(4)/kg). Thus M-CSF is not effective for expanding a pool of circulating hematopoietic stem cells when administered at a conventional dose during hematologic recovery following chemotherapy.

Cytotoxic drug and cytotoxic drug/G-CSF mobilization of peripheral blood stem cells and their use for autografting.

We analysed 99 courses of leukapheresis after the use of cytotoxic drugs or cytotoxic drugs plus G-CSF (cytotoxic/G-CSF) to mobilize peripheral blood stem cells (PBSC) in 68 patients with hematologic or solid malignancies. Mean yields of granulocyte-macrophage progenitor cells (CFU-GM) with cytotoxic/G-CSF mobilization were significantly higher than those with cytotoxic mobilization (18.6 vs 8.40 x 10(4)/kg). The optimal timing of collection was different between these two mobilizations; the mean number of days to a peak level of circulating CFU-GM after cytotoxic/G-CSF mobilization was less than that after cytotoxic mobilization (24.2 vs 27.7 days). The leukocyte level on the day of peak CFU-GM was significantly higher in cytotoxic/G-CSF mobilization than that in cytotoxic mobilization (mean 12.8 vs 2.7 x 10(9)/l), whereas the platelet level was not different (mean 132 vs 125 x 10(9)/l). Increasing patient age was not a major adverse factor for PBSC collection. Synchronous recovery of both leukocytes and platelets was critical for achieving a high CFU-GM yield in these two mobilizations. Following PBSC autotransplantation, the rate of trilineage hematologic reconstitution showed a significant correlation with the infused dose of CFU-GM, whether they were collected with cytotoxic or cytotoxic/G-CSF mobilization. These results suggest that G-CSF can expand the PBSC pool and that CFU-GM yield after cytotoxic/G-CSF mobilization may predict trilineage hemopoietic reconstitution after ABSCT, as well as cytotoxic mobilization.

Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia.

The safety and efficacy of myeloablative therapy followed by autologous peripheral blood stem cell transplantation (ABSCT) for acute myelogenous leukemia (AML) were evaluated in 60 patients. Peripheral blood stem cells (PBSC) were collected during recovery after consolidation chemotherapy. High-dose chemotherapy consisting of busulfan (16 mg/kg), etoposide (40 mg/kg), and cytosine arabinoside (3 g/m2 x 4) (BEA regimen) was used for pretransplant conditioning in 13 patients. For the remaining 47 patients, granulocyte colony-stimulating factor (G-CSF) was administered concurrently with the BEA regimen during conditioning. Unpurged, cryopreserved PBSC containing a median number of 5.4 x 10(8) MNC/kg or 12 x 10(4) CFU-GM/kg were reinfused at transplantation. The median number of days to granulocytes exceeding 500/microl and last platelet transfusion were 15 (8-44) and 24 (0->180), respectively. The 3-year probabilities of disease-free survival (DFS) and relapse were 78.6 and 21.4% for patients transplanted in first remission, 29.6 and 64.4% for those in second or third remission, and 11.1 and 77.8% for those in relapse, respectively. There were no transplant-related deaths within 100 days of transplantation. Age, disease status at transplantation, and number of induction chemotherapies to first complete remission were risk factors affecting the outcome of ABSCT. These results of ABSCT for AML in first remission warrant a prospective study of ABSCT as post-remission therapy.

Identification and characterization of a Drosophila homologue of the yeast UBC9 and hus5 genes.

The yeast UBC9 and hus5 gene products have been identified as putative E2 members of the ubiquitin-conjugating enzyme (UBC) family and have been shown to play an essential role in cell cycle progression. We have identified a Drosophila Ubc9/Hus5 homologue (termed dUBC9) in an attempt to identify proteins that interact with the amino-terminal transcriptional repression domain of the Groucho corepressor by use of the yeast two-hybrid system. The predicted dUBC9 protein consists of 159 amino acids and shows 85, 68, and 54% amino acid sequence identities with human UBC9 homologue, Schizosaccharomyces pombe Hus5, and Saccharomyces cerevisiae Ubc9 proteins, respectively. Expression of dUBC9 cDNA complements a temperature-sensitive ubc9-1 mutation of S. cerevisiae to fully restore normal growth, indicating that the dUBC9 protein can act as a substitute for the yeast Ubc9 protein. The dUBC9 transcripts were about 1.2 kb and were detected at all stages of Drosophila development and in ovaries and Schneider cells. However, an increased level was observed in early embryos and ovaries. The dUBC9 gene is present as a single copy in the genome and localized in segment 21C-D on the left arm of the second chromosome.

Role of interleukin-4 in the negative regulation of proliferation of chronic myelomonocytic leukemia cells.

We studied the effects of interleukin-4 (IL-4) on the spontaneous proliferation of chronic myelomonocytic leukemia (CMMoL) cells in vitro to clarify whether IL-4 can act as a negative regulator of hematopoiesis. The results clearly show that IL-4 suppressed spontaneous DNA synthesis and colony formation by CMMoL cells in vitro. Colony formation by CMMoL cells was substantially suppressed by adding either an anti-IL-6 or anti-GM-CSF antibody to the colony assay system. This suppression was abrogated by the treatment of IL-4 with an anti-IL-4 antibody. Furthermore, the production of IL-6 or GM-CSF was markedly inhibited by adding IL-4 to the culture system. These observations indicate that IL-4 can act as a negative regulator for the autocrine growth of CMMoL cells by inhibiting their production of IL-6 and/or GM-CSF.

Changes in expression of the mouse homologues of KIAA genes after subchronic methamphetamine treatment.

Amphetamine abuse may be associated with adaptive changes in gene expression in the brain. In the present study, a newly developed cDNA array system comprising mouse KIAA (mKIAA) cDNA clones was used to examine the gene expression affected by chronic methamphetamine treatment. Approximately 800 mKIAA clones were blotted onto a nylon membrane and hybridized with 33P-labeled cDNA derived from mRNAs isolated from the whole brains of mice that had been treated daily with saline or methamphetamine (2 mg/kg, i.p.) for 2 weeks. The arrays displayed robust hybridization for almost all transcripts. The results obtained from five experiments were averaged, each performed with triplicate samples. Several clones were chosen as positive candidates for methamphetamine-induced changes; however, only Per2 and mKIAA0099 genes showed a significantly increased expression (P < .05). Subsequently, with the focus on the period-related proteins, the expression of these proteins in various parts of the rat brain were assessed by immunoblot analysis. Chronic administration of methamphetamine (8 mg/kg, i.p., for 10 days) caused increased Per2 protein expression in the hippocampus. Interestingly, chronic methamphetamine treatment at a lower dose (4 mg/kg, i.p., for 10 days) induced an increase in SCN circadian oscillatory protein (SCOP) expression, also in the hippocampus. These data suggest that long-lasting alterations of the period-related gene expressions in the hippocampus might play an important role in methamphetamine addiction.

The effects of intracerebroventricularly injected corticotropin-releasing factor (CRF) on the central nervous system: behavioural and biochemical studies.

Intracerebroventricularly (ICV) administered corticotropin-releasing factor (CRF) produces behavioural activation in rats. The present study was designed to investigate the effects of ICV administered CRF on not only locomotor activity, but also the turnover rates of dopamine (DA) and norepinephrine (NE) in various discrete brain regions in rats. ICV administration of 1 microgram CRF produced a significant increase in locomotor activity, while ICV administration of 10 micrograms CRF caused slow stereotypy with prominent grooming. The 3,4-dihydroxyphenylacetic acid/DA ratio, e.g. DA utilization, was increased in the frontal cortex (FC), striatum, hippocampus (HIPP) and amygdala. DA utilization in the FC increased in a dose dependent manner, suggesting that the hyperactivity of the mesocortical DA system is relevant to the grooming response. The 3-methoxy-4-hydroxy-phenylglycol/NE ratio was increased in the FC and HIPP, indicating the involvement of the dorsal NE pathway in ICV CRF-induced behavioural changes in rats. These findings are discussed in connection with the hypothesis that CRF produces behavioural changes consistent with increasing emotionality, especially anxiety, and may serve as a neuroendocrine modulator of stress-enhanced behaviour.

The effects of corticotropin-releasing hormone on peptidergic neurons in the rat forebrain.

Our previous study showed that intracerebroventricular (ICV) administration of corticotropin-releasing hormone (CRH) produced a significant increase in locomotor activity at a dose of 1 microgram and slow stereotypy with prominent grooming at a dose of 10 micrograms. In addition, the ICV administration of CRH caused a significant increase in dopamine (DA) and norepinephrine turnover (NE) in various forebrain regions. The present study was designed to investigate the effects of the ICV administration of CRH on cholecystokinin (CCK), neuropeptide Y (NPY), somatostatin (SOM) and gamma-amino butyric acid (GABA) in the rat forebrain. The ICV administration of 1 and 10 micrograms CRH caused a marked reduction in CCK-like immunoreactivity (CCK-LI), NPY-LI and SOM-LI in the medial frontal cortex (MFC) and anterior cingulate cortex (Ant.CC), whereas it induced an increment of NPY-LI in the nucleus accumbens (NAc) and striatum. Increased SOM-LI and decreased NPY-LI were observed in the hippocampus following the ICV administration of CRH at both doses. The ICV administration of CRH caused a significant decrease in the BAGA content in the MFC, ant.CC, NAc and striatum. Taken together with our previous findings, these results indicate that the ICV administration of CRH induced classical neurotransmitter and neuropeptide abnormalities in the central nervous system which resulted increased emotionality, especially anxiety, in rats.